Injection paradigm for administration of botulinum toxins

ABSTRACT

Disorders such as headaches can be treated by administration of a botulinum toxin to a patient suffering therefrom, such as a migraine headache. A combined a fixed site/fixed dose and an optional follow the pain variable dosage and injection site paradigm is disclosed for optimizing clinical effectiveness of botulinum toxin administration for patients suffering headache, particularly chronic migraine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.15/067,515, filed Mar. 11, 2016, now U.S. Pat. No. 10,111,938, whichclaims the benefit of U.S. Provisional patent application No. 62/132,689filed Mar. 13, 2015 and may be related to U.S. patent application Ser.No. 13/075,485 filed Mar. 30, 2011, now U.S. Pat. No. 8,501,195,incorporated entirely by reference.

FIELD

Embodiments of the present invention relate to the treatment of variousdisorders, specifically to injection administration protocols utilizingbotulinum neurotoxins. In particular, the present disclosure is directedto methods for improving administration protocols for treatment ofchronic migraine.

BACKGROUND

It is known that botulinum toxins can be utilized to treat a variety ofdisorders. Examples include U.S. Pat. No. 5,714,468 (migraine) issuedFeb. 3, 1998; Published U.S. Patent Application No. 2005019132(headache), Ser. No. 11/039,506, filed Jan. 18, 2005; Published U.S.Patent Application No. 20050191320 (medication overuse headache), Ser.No. 10/789,180, filed Feb. 26, 2004; and U.S. Pat. No. 7,811,587(neuropsychiatric disorders), issued Oct. 12, 2010; all incorporatedentirely by reference.

An example of a disorder treatable with botulinum toxins is chronicmigraine (CM), a disabling headache disorder, affecting 1.3% to 2.4% ofthe general population and considered the most common type of primarychronic daily headache in the United States. CM is linked withsuffering, disability, and medication overuse, and only one third of CMpatients use headache prophylactic medication. Few headache preventivetreatments have been investigated for patients with CM. Thus thereremains a need for optimized and targeted methodologies to treat thismalady in particular, specific and useful injection and dosage paradigmsfor utilizing botulinum toxins to treating CM.

SUMMARY

In one embodiment, the present invention teaches a method forprophylactically treating a headache in a patient suffering from chronicmigraine headaches, the method comprises of local administration of aclostridial neurotoxin, such as a botulinum neurotoxin, to thefrontalis, corrugator, procerus, occipitalis, temporalis, trapezius andcervical paraspinal muscles of the patient that suffers from themigraine headache, where the botulinum neurotoxin is administered, tothe frontalis at about twenty units divided among four sites ofinjection, to the corrugator at about ten units divided among two sitesof injection; to the procerus at about five units to one site ofinjection; to the occipitalis at about thirty units divided among sixsites of injection to about forty units divided among eight sites ofinjection; to the temporalis at about forty units divided among eightsites of injection up to fifty units divided among ten sites ofinjection; to the trapezius at about thirty units divided among sixsites of injection up to about fifty units divided among ten sites ofinjection and to the cervical paraspinal muscles at about twenty unitsdivided among four sites of injection, and where the botulinumneurotoxin is injected at 31 to 39 injection sites.

In some aspects, the present disclosure is directed to a method forreducing the occurrence or alleviating a headache in a patient sufferingfrom chronic migraine headaches in a patient with chronic migraineheadaches, the method comprises: localizing one or more administrationtarget; isolating the one or more administration target; administering atherapeutically effective amount of a clostridial toxin to the isolatedone or more administration target; wherein the one or moreadministration target comprises the frontalis, corrugator, procerus,occipitalis, temporalis, trapezius and cervical paraspinal muscles;wherein the administrating step is by injection and wherein theadministering step comprises limiting the injection to a defined tissuedepth and injection angle.

In some aspects, the present disclosure is directed to a method forimproving efficacy of headache treatment by a clostridial toxin, such asa botulinum toxin, in a patient in need thereof by minimizing adverseeffects associated with clostridial toxin administration, comprisinglocalizing one or more administration target, isolating the one or moreadministration target, administering a therapeutically effective amountof the clostridial toxin to the isolated one or more administrationtarget, wherein the administrating step is by injection and wherein theadministering step comprises limiting the injection to a defined tissuedepth and injection angle. In some embodiments, the adverse effectsinclude ptosis, neck pain/weakness, headache, or combinations thereof.In some embodiments, the method further comprises evaluating the patientfor manifestations of adverse effects prior to the locating, isolatingand administrating steps. In some embodiments, the method furthercomprises informing the patient of the manifestation of adverse effects.

In some aspects, the present disclosure provides a method for minimizingadverse effects associated with the administration of a clostridialtoxin, such as a botulinum toxin, for treating or alleviating a headachein a patient with chronic migraine, the method comprises locating one ormore administration target, isolating the one or more administrationtarget, administering a therapeutically effective amount of aclostridial toxin to the isolated one or more administration target;wherein the administrating step is by injection and wherein theadministering step comprises limiting the injection to a defined tissuedepth and injection angle. In some embodiments, the adverse effectscomprise ptosis, neck pain and/or weakness, headache, or combinationsthereof. In some embodiments, the present method further increasespatient compliance in timely getting re-treatment.

The present method also comprises assessing a patient for pre-existingconditions prior to clostridial toxin treatment for expectationmanagement, selecting a suitable injection protocol to minimizeaggravating the pre-existing conditions or delaying the clostridialtoxin administration until the pre-existing conditions improve. In someembodiments, the pre-existing conditions include ptosis, neck pain orweakness, headache, or combinations thereof.

The present method further comprises identifying a patient who may beprone to having clostridial toxin administration associated adverseeffects, informing the patient of the risk of adverse effects andselecting a suitable injection protocol to prevent or minimize the riskof adverse effects. In some embodiments, the adverse effects includeptosis, neck pain or weakness, headache, or combinations thereof.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

The following drawings are presented to illustrate aspects and featuresof embodiments of the present invention.

FIGS. 1A and 1B show the forehead anatomy, identifying one or moreadministration target sites thereof in accordance with one embodiment ofthe present injection paradigm;

FIGS. 2A-2D detail the anatomy, the administration sites, and injectiontechnique for administrating a botulinum toxin into the corrugatormuscle in accordance with aspects of the present method;

FIGS. 3A-3D detail the anatomy, the administration site, and injectiontechnique for administrating a botulinum toxin into the procerus musclein accordance with aspects of the present method;

FIGS. 4A-4D detail the anatomy, the administration sites, and injectiontechnique for administrating a botulinum toxin into the frontalis musclein accordance with aspects of the present method;

FIGS. 5 A-5D show some examples of ptosis;

FIGS. 6A-6D detail the anatomy, the administration sites, and injectiontechnique for administrating a botulinum toxin into the temporalismuscle in accordance with aspects of the present method;

FIGS. 7A and 7B show the back-of-head and neck anatomy, identifying oneor more administration target sites thereof in accordance with aspectsof the present injection paradigm;

FIGS. 8A-8B show the administration sites and injection technique foradministrating a botulinum toxin into the occipitalis muscle inaccordance aspects of the present method;

FIGS. 9A-9B show the administration sites and injection technique foradministrating a botulinum toxin into the cervical paraspinal musclegroup in accordance aspects of the present method;

FIGS. 10A-10B show the administration sites and injection technique foradministrating a botulinum toxin into the trapezius muscle in accordanceaspects of the present method; and

FIG. 11 is a diagram for assessing a patient's neck pain/weakness inaccordance with aspects of the present method.

DESCRIPTION

In certain embodiments, the dose of a botulinum toxin used according toembodiments of the present invention is less than the amount ofbotulinum toxin that would be used to paralyze a muscle, because anintent of a method according to embodiments of the present invention isnot to paralyze a muscle but to reduce a pain sensory output fromsensory neurons located in or on a muscle, or in or under the skin.

The following definitions apply herein:

“About” or “approximately” as used herein means within an acceptableerror range for the particular value as determined by one of ordinaryskill in the art, which will depend in part on how the value is measuredor determined, (i.e., the limitations of the measurement system). Forexample, “about” can mean within 1 or more than 1 standard deviations,per practice in the art. Where particular values are described in theapplication and claims, unless otherwise stated, the term “about” meanswithin an acceptable error range for the particular value.

“Administration”, or “to administer” means the step of giving (i.e.administering) a botulinum toxin to a subject, or alternatively asubject receiving a pharmaceutical composition. The present method canbe performed via administration routes including intramuscular,non-intramuscular, intra-articular, extra-articular, peri-articular,intradermal, subcutaneous administration, topical administration (usingliquid, cream, gel or tablet formulation), intrathecal administration,intraperitoneal administration, intravenous infusion, implantation (forexample, of a slow-release device such as polymeric implant orminiosmotic pump), or combinations thereof.

“Alleviating” means a reduction of an undesirable condition or itssymptoms, for example headache intensity or headache-associatedsymptoms. Thus, alleviating includes some reduction, significantreduction, near total reduction, and total reduction. An alleviatingeffect may not appear clinically for between 1 to 7 days afteradministration of a clostridial derivative to a patient or sometimethereafter.

“Botulinum toxin” means a neurotoxin produced by Clostridium botulinum,as well as a botulinum toxin (or the light chain or the heavy chainthereof) made recombinantly by a non-Clostridial species. The term“botulinum toxin”, as used herein, encompasses the botulinum toxinserotypes A, B, C₁, D, E, F and G, and their subtypes and any othertypes of subtypes thereof, or any re-engineered proteins, analogs,derivatives, homologs, parts, sub-parts, variants, or versions, in eachcase, of any of the foregoing. “Botulinum toxin”, as used herein, alsoencompasses a “modified botulinum toxin”. Further “botulinum toxin” asused herein also encompasses a botulinum toxin complex, (for example,the 300, 600 and 900 kDa complexes), as well as the neurotoxic componentof the botulinum toxin (150 kDa) that is unassociated with the complexproteins.

“Clostridial derivative” refers to a molecule which contains any part ofa clostridial toxin. As used herein, the term “clostridial derivative”encompasses native or recombinant neurotoxins, recombinant modifiedtoxins, fragments thereof, a Targeted vesicular Exocytosis Modulator(TEM), or combinations thereof.

“Clostridial toxin” refers to any toxin produced by a Clostridial toxinstrain that can execute the overall cellular mechanism whereby aClostridial toxin intoxicates a cell and encompasses the binding of aClostridial toxin to a low or high affinity Clostridial toxin receptor,the internalization of the toxin/receptor complex, the translocation ofthe Clostridial toxin light chain into the cytoplasm and the enzymaticmodification of a Clostridial toxin substrate.

“Effective amount” as applied to the biologically active ingredientmeans that amount of the ingredient which is generally sufficient toinduce a desired change in the subject.

“Implant” means a controlled release (e.g., pulsatile or continuous)composition or drug delivery system. The implant can be, for example,injected, inserted or implanted into a human body.

“Local administration” means administration of a clostridial derivativeto or to the vicinity of a symptomatic site in a patient by anon-systemic route. Thus, local administration excludes systemic routesof administration, such as intravenous or oral administration.

“Peripheral administration” means administration to a location away froma symptomatic location, as opposed to a local administration.

“TEMs”, abbreviated for Targeted Exocytosis Modulators are retargetedendopeptidases that direct the catalytic activity of the light chain tospecific types of neuronal cells or to target cells that were notaffected by botulinum toxins expanding the beneficial clinical effect ofinhibition of exocytosis in several human diseases.

“Treating” or “treatment” means to prevent, reduce the occurrence,alleviate, or to eliminate an undesirable condition, for exampleheadache, either temporarily or permanently.

“Therapeutically effective amount” refers to an amount sufficient toachieve a desired therapeutic effect. The therapeutically effectiveamount usually refers to the amount administered per injection site perpatient treatment session, unless indicated otherwise.

Disclosed herein are embodiments of an administration paradigm forbotulinum neurotoxins. In some embodiments, the method can includespecific administration locations and dosage amounts of a botulinumtoxin to treat various disorders, including, for example, chronicmigraine (CM), Medication overuse (MOU), neuropsychiatric (ND)disorders, and the like. In certain embodiments of the invention, thedisorder can be treated by intramuscular administration of the toxin inspecific amounts or ranges of amounts to specific sites within the uppertorso of the patient. In certain embodiments, such sites can include,for example, the head, the neck, one or both shoulders, in both theanterior or posterior positions.

In some embodiments, the clostridial derivative of the present methodincludes a native, recombinant clostridial toxin, recombinant modifiedtoxin, fragments thereof, targeted exocytosis modulators (TEMs), orcombinations thereof. In some embodiments, the clostridial derivative isa botulinum toxin. In alternative embodiments, the clostridialderivative is a TEM.

In some embodiments, the botulinum neurotoxin can be a modifiedneurotoxin, that is a botulinum neurotoxin which has at least one of itsamino acids deleted, modified or replaced, as compared to a nativetoxin, or the modified botulinum neurotoxin can be a recombinantproduced botulinum neurotoxin or a derivative or fragment thereof. Incertain embodiments, the modified toxin has an altered cell targetingcapability for a neuronal or non-neuronal cell of interest. This alteredcapability is achieved by replacing the naturally-occurring targetingdomain of a botulinum toxin with a targeting domain showing a selectivebinding activity for a non-botulinum toxin receptor present in anon-botulinum toxin target cell. Such modifications to a targetingdomain result in a modified toxin that is able to selectively bind to anon-botulinum toxin receptor (target receptor) present on anon-botulinum toxin target cell (re-targeted). A modified botulinumtoxin with a targeting activity for a non-botulinum toxin target cellcan bind to a receptor present on the non-botulinum toxin target cell,translocate into the cytoplasm, and exert its proteolytic effect on theSNARE complex of the target cell. In essence, a botulinum toxin lightchain comprising an enzymatic domain is intracellularly delivered to anydesired cell by selecting the appropriate targeting domain.

In some embodiments, the clostridial derivative is a botulinum toxin,which is selected from the group consisting of botulinum toxin types A,B, C₁, D, E, F and G. In one embodiment, the clostridial derivative ofthe present method is a botulinum toxin type A. The botulinum toxin canbe a recombinant botulinum neurotoxin, such as botulinum toxins producedby E. coli.

The clostridial derivative, such as a botulinum toxin, for use accordingto the present invention can be stored in lyophilized, vacuum dried formin containers under vacuum pressure or as stable liquids. Prior tolyophilization the botulinum toxin can be combined with pharmaceuticallyacceptable excipients, stabilizers and/or carriers, such as, forexample, albumin, or the like. Acceptable excipients or stabilizersinclude protein excipients, such as albumin or gelatin, or the like, ornon-protein excipients, including poloxamers, saccharides, polyethyleneglycol, or the like. In embodiments containing albumin, the albumin canbe, for example, human serum albumin or recombinant human albumin, orthe like. The lyophilized material can be reconstituted with a suitableliquid such as, for example, saline, water, or the like to create asolution or composition containing the botulinum toxin to beadministered to the patient.

In some embodiments, to increase the resident time of the clostridialderivative in the joint, the clostridial derivative is provided in acontrolled release system comprising a polymeric matrix encapsulatingthe clostridial derivative, wherein fractional amount of the clostridialderivative is released from the polymeric matrix over a prolonged periodof time in a controlled manner. Controlled release neurotoxin systemshave been disclosed for example in U.S. Pat. Nos. 6,585,993; 6,585,993;6,306,423 and 6,312,708, each of which is hereby incorporated byreference in its entirety.

The therapeutically effective amount of the clostridial derivative, forexample a botulinum toxin, administered according to the present methodcan vary according to the potency of the toxin and particularcharacteristics of the condition being treated, including its severityand other various patient variables including size, weight, age, andresponsiveness to therapy. The potency of the toxin is expressed as amultiple of the LD₅₀ value for the mouse, one unit (U) of toxin beingdefined as being the equivalent amount of toxin that kills 50% of agroup of 18 to 20 female Swiss-Webster mice, weighing about 20 gramseach.

The therapeutically effective amount of the botulinum toxin according tothe present method can vary according to the potency of a particularbotulinum toxin, as commercially available Botulinum toxin formulationsdo not have equivalent potency units. For example, one unit of BOTOX®(onabotulinumtoxinA), a botulinum toxin type A available from Allergan,Inc., has a potency unit that is approximately equal to 3 to 5 units ofDYSPORT® (abobotulinumtoxinA), also a botulinum toxin type A availablefrom Ipsen Pharmaceuticals. In some embodiments, the amount ofabobotulinumtoxinA, (such as DYSPORT®), administered in the presentmethod is about three to four times the amount of onabotulinumtoxinA(such as BOTOX®) administered, as comparative studies have suggestedthat one unit of onabotulinumtoxinA has a potency that is approximatelyequal to three to four units of abobotulinumtoxinA. MYOBLOC®, abotulinum toxin type B available from Elan, has a much lower potencyunit relative to BOTOX®. In some embodiments, the botulinum neurotoxincan be a pure toxin, devoid of complexing proteins, such as XEOMIN®(incobotulinumtoxinA). One unit of incobotulinumtoxinA has potencyapproximately equivalent to one unit of onabotulinumtoxinA. The quantityof toxin administered, and the frequency of its administration will beat the discretion of the physician responsible for the treatment andwill be commensurate with questions of safety and the effects producedby a particular toxin formulation.

The amount of the botulinum toxin administered according to a methodwithin the scope of embodiments of the invention can vary according tothe particular characteristics of the pain being treated, including itsseverity and other various patient variables including size, weight,age, and responsiveness to therapy.

To guide the practitioner, typically, no less than about 1 unit and nomore than about 25 units of a botulinum toxin type A (such as BOTOX®) isadministered per injection site per patient treatment session. For abotulinum toxin type A such as DYSPORT®, no less than about 2 units andno more than about 25 units of the botulinum toxin type A areadministered per injection site, per patient treatment session. For abotulinum toxin type A such as DYSPORT®, no less than about 2 units andno more than about 125 units of the botulinum toxin type A areadministered per injection site, per patient treatment session. For abotulinum toxin type B such as MYOBLOC®, no less than about 40 units andno more than about 1500 units of the botulinum toxin type B areadministered per injection site, per patient treatment session.

Preferably, for BOTOX® no less than about 2 units and no more about 20units of a botulinum toxin type A are administered per injection siteper patient treatment session; for DYSPORT® no less than about 4 unitsand no more than about 100 units are administered per injection site perpatient treatment session; and; for MYOBLOC®, no less than about 80units and no more than about 1000 units are administered per injectionsite, per patient treatment session.

More preferably, for BOTOX® no less than about 5 units and no more about15 units of a botulinum toxin type A; for DYSPORT® no less than about 20units and no more than about 75 units, and; for MYOBLOC®, no less thanabout 200 units and no more than about 750 units are, respectively,administered per injection site, per patient treatment session.

Generally, the total amount of BOTOX®, DYSPORT® or MYOBLOC®, suitablefor administration to a patient according to the methods of theinvention disclosed herein should not exceed about 300 units, about1,500 units or about 15,000 units respectively, per treatment session.

The treatment effects of the botulinum toxin can persist for betweenabout 1 month and about 5 years.

Embodiments of the present disclosure provide a targeted, fixedinjection paradigm directed to a specific set of muscles with a specificminimum number and volume of injections, and further provides for theadditional/optional administration of additional botulinum toxin tospecific site of selected muscles. In one embodiment, the fixed dosage(that is, a minimum dosage amount in accordance with the fixed amountsand locations specified in a package insert or prescribing information)of botulinum toxin is administered to the frontalis, corrugator,procerus, occipitalis, temporalis, trapezius and cervical paraspinalmuscles of a patient, and further a variable amount of additionalbotulinum toxin can be added to four or less of the seven head/neckareas such that the total amount of botulinum toxin administered doesnot exceed a maximum total dosage as indicated in the package insert orprescribing information accompanying a botulinum toxin-containingmedicament.

The botulinum toxin can be selected from the group consisting ofbotulinum toxin types A, B, C, D, E, F and G. Botulinum toxin type A isa preferred botulinum toxin. The botulinum toxin can be administered inan amount of between about 1 unit and about 3,000 units, or betweenabout 2 units and about 2000 units, or between about 5 units and about1000 units, or between about 10 units and about 500 units, or betweenabout 15 units and about 250 units, or between about 20 units and about150 units, or between 25 units and about 100 units, or between about 30units and about 75 units, or between about 35 units and about 50 units,or the like, and the alleviation of the symptoms can persist for betweenabout 1 month and about 5 years.

In one embodiment, a method is disclosed that utilizes a dose andinjection paradigm of 155 units of BOTOX® (typically provided as 100Units of Clostridium botulinum type A neurotoxin complex, with 0.5 mg ofhuman serum albumin, and 0.9 mg of sodium chloride in a sterile,vacuum-dried state for reconstitution), administered as 31 fixed-site,fixed-dose (5 units) injections, and an optional 40 units in up to 8additional injection sites using a follow-the-pain regimen per treatmentcycle (for up to 39 injection sites and up to 195 units total). Thetotal dose is divided across 7 head/neck muscles and is repeated every12 weeks.

In an embodiment, a method for treating a migraine such as, for example,CM, can encompass administration of a botulinum toxin to 31 fixedinjection sites across seven head/neck muscles. Optionally, up to 8additional injection sites into three specific muscles, where thesethree muscles are subset of the above seven head/neck muscles, areadministered utilizing a follow-the pain regimen to provide flexibilityin the dose/muscle for the three muscles, to address individual patientneeds. In particular embodiments, a minimum of 155 units of a botulinumtoxin type A up to about 195 units of a botulinum toxin type A, areadministered in accordance with a particular injection paradigm hereindisclosed.

In a specific embodiment, a method for treating CM comprises the step oflocal administration of a botulinum neurotoxin to the frontalis,corrugator, procerus, occipitalis, temporalis, trapezius and cervicalparaspinal muscles of the CM patient such that the botulinum neurotoxinis administered to the frontalis at about twenty units divided amongfour sites of injection, to the corrugator at about ten units dividedamong two sites of injection, to the procerus at about five units to onesite of injection, to the occipitalis at about thirty units dividedamong six sites of injection to about forty units divided among eightsites of injection; to the temporalis at about forty units divided amongeight sites of injection up to fifty units divided among ten sites ofinjection, to the trapezius at about thirty units divided among sixsites of injection up to about fifty units divided among ten sites ofinjection and to the cervical paraspinal muscles at about twenty unitsdivided among four sites of injection, such that the total amount ofbotulinum neurotoxin administered is from about 155 units to about 195units injected at from 31 to 39 injection sites, respectively.

Embodiments of the invention can also be used as part of adetoxification protocol whereby a patient who is being weaned off acutepain medications is facilitated in this goal by concurrentadministration of a botulinum toxin. Additional embodiments of theinvention can be used to treat other chronic pain conditions, including,for example, back pain, neuropathic pain, allodynia, fibromyalgia, andthe like.

In an embodiment, a method for treating an MOU patient can encompassadministration of a botulinum toxin to 31 fixed injection sites acrossseven head/neck muscles. Optionally, up to 8 additional injection sitesinto three specific muscles, where these three muscles are subset of theabove seven head/neck muscles, are administered utilizing a follow-thepain regimen to provide flexibility in the dose/muscle for the threemuscles, to address individual patient needs. In particular embodiments,a minimum of 155 units of a botulinum toxin type A up to about 195 unitsof a botulinum toxin type A, are administered in accordance with aparticular injection paradigm herein disclosed.

In a specific embodiment, a method for treating MOU comprises the stepof local administration of a botulinum neurotoxin to the frontalis,corrugator, procerus, occipitalis, temporalis, trapezius and cervicalparaspinal muscles of the MOU patient such that the botulinum neurotoxinis administered to the frontalis at about twenty units divided amongfour sites of injection, to the corrugator at about ten units dividedamong two sites of injection, to the procerus at about five units to onesite of injection, to the occipitalis at about thirty units dividedamong six sites of injection to about forty units divided among eightsites of injection; to the temporalis at about forty units divided amongeight sites of injection up to fifty units divided among ten sites ofinjection, to the trapezius at about thirty units divided among sixsites of injection up to about fifty units divided among ten sites ofinjection and to the cervical paraspinal muscles at about twenty unitsdivided among four sites of injection, such that the total amount ofbotulinum neurotoxin administered is from about 155 units to about 195units injected at from 31 to 39 injection sites, respectively.

In an embodiment, a method for treating depression can encompassadministration of a botulinum toxin to 31 fixed injection sites acrossseven head/neck muscles. Optionally, up to 8 additional injection sitesinto three specific muscles, where these three muscles are subset of theabove seven head/neck muscles, are administered utilizing a follow-thepain regimen to provide flexibility in the dose/muscle for the threemuscles, to address individual patient needs. In particular embodiments,a minimum of 155 units of a botulinum toxin type A up to about 195 unitsof a botulinum toxin type A, are administered in accordance with aparticular injection paradigm herein disclosed.

In a specific embodiment, a method for treating neuropsychiatricdisorders (ND) such as, for example, depression, in a patient in needthereof comprises the step of local administration of a botulinumneurotoxin to the frontalis, corrugator, procerus, occipitalis,temporalis, trapezius and cervical paraspinal muscles of the patientsuch that the botulinum neurotoxin is administered to the frontalis atabout twenty units divided among four sites of injection, to thecorrugator at about ten units divided among two sites of injection, tothe procerus at about five units to one site of injection, to theoccipitalis at about thirty units divided among six sites of injectionto about forty units divided among eight sites of injection; to thetemporalis at about forty units divided among eight sites of injectionup to fifty units divided among ten sites of injection, to the trapeziusat about thirty units divided among six sites of injection up to aboutfifty units divided among ten sites of injection and to the cervicalparaspinal muscles at about twenty units divided among four sites ofinjection, such that the total amount of botulinum neurotoxinadministered is from about 155 units to about 195 units injected at from31 to 39 injection sites, respectively.

A method for treating or reducing the occurrence of a headache in apatient with chronic migraine has been disclosed in U.S. Pat. No.8,501,195 to Turkel (hereinafter “the '195 patent” or “the Turkelpatent”).

The '195 patent teaches a method for treating a headache in a patientsuffering from chronic migraine headaches, the method essentiallyconsisting of local administration of a botulinum neurotoxin to thefrontalis, corrugator, procerus, occipitalis, temporalis, trapezius andcervical paraspinal muscles of the patient that suffers from themigraine headache, where the botulinum neurotoxin is administered, tothe frontalis at about twenty units divided among four sites ofinjection, to the corrugator at about ten units divided among two sitesof injection; to the procerus at about five units to one site ofinjection; to the occipitalis at about thirty units divided among sixsites of injection to about forty units divided among eight sites ofinjection; to the temporalis at about forty units divided among eightsites of injection up to fifty units divided among ten sites ofinjection; to the trapezius at about thirty units divided among sixsites of injection up to about fifty units divided among ten sites ofinjection and to the cervical paraspinal muscles at about twenty unitsdivided among four sites of injection, and where the botulinumneurotoxin is injected at 31 to 39 injection sites.

The treatment taught by the '195 patent (hereinafter “the '195treatment” or “the Turkel treatment”) has been practiced by health carepractitioners with high efficacy to treat or reduce the occurrence of aheadache in a patient with chronic migraine. In one embodiment, the '195patent teaches a method for treating chronic migraine that utilizes adose and injection paradigm of 155 units of onabotulinumtoxinA,administered as 31 fixed-site, fixed-dose (5 units per) injections, andan optional 40 units in up to 8 additional injection sites using afollow-the-pain regimen per treatment cycle (for up to 39 injectionsites and up to 195 units total). The total dose is divided across 7head/neck muscles and is repeated every 12 weeks.

The inventors of the present disclosure have discovered that complianceto the treatment protocol of “a minimum dose of 155 units divided across7 head/neck muscles and repeated every 12 weeks” is not optimallyconsistent due to adverse effects which will be described herein. Theseadverse effects are attributable to improper, imprecise or inaccurateimplementation of the '195 protocol, which results in inadvertent andundesirable administration of the botulinum toxin into an area adjacentto an administration target site and/or too deep injections intosensitive structures. Because of these adverse effects, selectedadministration targets of the '195 treatment method may be intentionallyleft out (such as for example some forehead and neck muscles), whichreduces the efficacy of the treatment method. These adverse effects mayalso discourage patients from timely seeking re-treatments. This delayfurther reduces the efficacy of the headache treatment.

In some aspects, the present disclosure provides a method for minimizingadverse effects associated with the administration of a botulinum toxinfor treating or alleviating a headache in a patient with chronicmigraine. In some embodiments, the adverse effects comprise ptosis, neckpain and/or weakness, headache, or combinations thereof. By minimizingthe adverse effects associated with administration of a botulinum toxinfor treating or alleviating a headache, the present method enhancesefficacy of the treatment and increases patient compliance in timelygetting re-treatment, which further increases efficacy treatment.

The present method also comprises assessing a patient for pre-existingconditions prior to botulinum toxin treatment for expectationmanagement, selecting a suitable injection protocol to minimizeaggravating the pre-existing conditions or delaying the botulinum toxinadministration until the pre-existing conditions improve. Thepre-existing conditions include ptosis, neck pain or weakness, headache,or combinations thereof.

The present method further comprises identifying a patient who may beprone to having botulinum toxin administration associated adverseeffects, including ptosis, neck pain or weakness, headache, orcombination thereof, informing the patient of the risk of adverseeffects, selecting a suitable injection protocol to prevent or minimizethe risk of adverse effects, or delay the botulinum toxin until the riskof adverse effects is reduced.

To increase efficacy of botulinum toxin treatment for headache/migraineand/or to minimize or eliminate the above-identified adverse effects,the present method comprises locating the administration target,isolating the administration target so that the botulinum toxin isadministered only to the isolated target area without inadvertentlyimpacting an adjacent area; controlling the injection depth, and anglingthe needle as to aim away from sensitive structures. In someembodiments, the administration target includes the 7 head/neck musclestaught by the '195 patent.

FIGS. 1A and 1B show the forehead anatomy, identifying the location ofexemplary administration target sites, including the corrugator,procerus and frontalis muscles.

Corrugator:

In one exemplary embodiment, as shown schematically in FIG. 2C, thepresent method comprises local administration of a botulinum neurotoxinto the corrugator at about ten units divided among two sites ofinjection. As shown in FIG. 2A, the corrugator muscle is located about1.5 cm or ˜1 fingerbreadth above the medial inferior edge of the orbitalrim, a bony landmark which can be used to localize the corrugator. Thisdistance may vary depending on individual anatomy. Thus, administratingof the botulinum neurotoxin based solely on the approximated distance of1.5 cm or fingerbreadth approach may lead to inadvertent penetration ofthe frontalis muscle, which can result in brow ptosis. Furthermore,pointing the needle upward at a 45 degree angle laterally may alsoresult in inadvertent penetration of the frontalis. Corrugators are thinmuscles, thus injecting too deep can hit the periosteum and may triggera headache/migraine.

To minimize or prevent unwarranted side effects, in some embodiments,the present method comprises locating the corrugator, isolating thecorrugator to eliminate or minimize inadvertent injection to thefrontalis and administering a botulinum toxin to the corrugators. Asshown in FIG. 2A, the corrugator muscle is located about 1.5 cm or ˜1fingerbreadth above the medial inferior edge of the orbital rim, a bonylandmark which can be used to localize the corrugator. In someembodiments, the locating step comprises localizing the orbital rim andthe corrugator muscle situated in the proximity thereof. The corrugatorsproduce vertical lines on the portion of the skin below the head betweenthe brows, as seen in FIG. 2B. In some embodiments, the isolating stepcomprises providing patient instructions to furrow her/his brow, whichactivates the corrugator and causing medial and inferior movement of thebrow (FIG. 2B). In some embodiments, the isolating step furthercomprises palpating and pinching the corrugator muscle, holding thembetween the thumb and index finger, as shown in FIG. 2D. The corrugatorsare brow depressors, meaning they pull the brow down. They attach to thenasal frontal bone medially and the skin of the eye brow laterally. Tofurther minimize or eliminate brow ptosis, in some embodiments, theadministering step comprises targeting the belly of the corrugators(FIG. 2B). In some embodiments, the administrating step comprisesinjecting at a 90° angle into the belly of the corrugator muscles, asshown in FIGS. 2B and 2D. In some embodiments, the administering stepfurther comprises controlling the penetration depth of the needle suchthat it remains above the periosteum.

In some embodiments, the present disclosure discloses a method forminimizing or eliminating adverse effects associated with botulinumtoxin administration for treatment of headache, the method compriseslocating the corrugator muscle, isolating the corrugator muscle,administrating a botulinum neurotoxin to the corrugator muscle at aboutten units divided among two sites of injection, wherein the locatingstep comprises localizing the orbital rim and the corrugator muscle inthe proximity thereof, the isolating step comprises providing a patientinstructions to furrow her/his brow, palpating and pinching thecorrugator muscle, holding them between the thumb and index finger; andwherein the administrating step comprises superficially injecting at a90° degree angle into the corrugator muscle. In some embodiments,superficially injecting comprises controlling the penetration depth ofthe needle such that it remains above the periosteum.

Procerus:

In one exemplary embodiment, as shown schematically in FIG. 3C, thepresent method further comprises local administration of a botulinumneurotoxin to the procerus at about five units. As shown in FIG. 3A, theprocerus muscle is between the brows, and not in the forehead.Relatively, the base of the procerus is located approximately midwaybetween the two corrugators injections (FIGS. 3C and 2C). This distancemay vary depending on individual anatomy. Thus, administrating of thebotulinum neurotoxin based solely on the approximated distance approachmay lead to inadvertent penetration of the frontalis muscle, which canresult in medial brow depression. Injecting too high in the brow area inthe lower frontalis can also lead to brow ptosis. The procerus muscle isthin, thus injecting too deep can hit the periosteum and may trigger aheadache/migraine.

To minimize or prevent unwarranted side effects, in some embodiments,the present method comprises locating the procerus, isolating theprocerus to eliminate or minimize inadvertent injection to the frontalisand administering a botulinum toxin to the procerus. In someembodiments, the locating step comprises localizing the administrationsites for the corrugators as set forth above and finding the base of theprocerus located midway between the two corrugator injections. As shownin FIG. 3B, the procerus draws down the medial angle of the eyebrow andproduces transverse lines over the bridge of the nose. In someembodiments, the isolating step comprises providing a patientinstructions to furrow her/his brow, and using the resulting verticaland horizontal lines as orientation lines (FIG. 3B). In someembodiments, the administering step comprises targeting the belly of theprocerus muscle, which may be visible between the corrugator lines (FIG.3D). In some embodiments, the administrating step comprises injectingsuperficially at a 90° angle into the procerus, as shown in FIG. 3D. Insome embodiments, the administering step further comprises controllingthe penetration depth of the needle such that it remains above theperiosteum.

Frontalis:

In some embodiments, as shown schematically in FIG. 4C, the presentmethod further comprises local administration of a botulinum neurotoxinto the frontalis at about twenty units divided among four sites ofinjection. In some prior art protocol, to localize the medial frontalismuscle for administration of botulinum toxin, a line is drawn from themedial edge of the supraorbital rim and the muscle areas for injectionsare approximated about 1.5 cm (˜1 fingerbreadth) above the corrugatorinjection site. The lateral frontalis muscle is localized as the areaparallel and about 1.5 cm (˜1 fingerbreadth) lateral to the medialinjection area, which is approximately in line with the midpupillaryline or the lateral limbic line. All foreheads are different shapes andsizes. Thus, administrating of the botulinum neurotoxin based solely onthe approximated distance or fingerbreadth approach may lead to lowinjections, which can cause medial brow weakness and lateral browelevation. Furthermore, the frontalis muscles are elevator muscles,meaning that they pull the brow upward. Unduly, inadvertently orimproperly weakening these muscles may cause or exacerbate brow ptosis.The frontalis muscles are thin, thus injecting too deep can hit theperiosteum and may trigger a headache/migraine.

To minimize or prevent unwarranted side effects, including browweakness, brow elevation, brow ptosis, in some embodiments, the presentmethod comprises locating the frontalis muscle, isolating administrationtarget area within the frontalis and administering a botulinum toxin tothe frontalis. In some embodiments, the locating step comprises definingthe medial and lateral area for neurotoxin administration. In someembodiments, defining the medial muscle area comprises drawing a line upfrom the medial edge of the supraorbital rim and the administrationtarget areas are about 1.5 cm above the corrugator administration site.In some embodiments, the lateral muscle area for neurotoxinadministration is parallel and about 1.5 cm lateral to the medialadministration site. In some embodiments, the frontalis administrationsites are in line with the midpupillary line or the lateral limbic line.As set forth above, this approach alone may lead to low injections. Thefrontalis muscles are involved in drawing the scalp forward, creatingtransverse lines on the forehead as well as in raising eyebrow and skinover the root of the nose, as shown in FIG. 4B. In some embodiments, theisolating step comprises providing patient instructions to raisingher/his eyebrows and skin over the root of the nose, such as creating anexpression of surprise (FIG. 4B). In some embodiments, the isolatingstep comprises identifying the upper third of the forehead (FIG. 4D). Insome embodiments, the administrating step comprises angling the needlesuperiorly at a 45° angle into the frontalis muscle, as shown in FIG.4D. As the needle is angled at 45°, the medication delivery site may bedifferent from the administration site. In some embodiments, theadministration step comprises injecting superficially by controlling thepenetration depth of the needle such that it remains above theperiosteum. In some embodiments, a local and topical anesthetic isadministered before administration of the neurotoxin to minimizediscomfort.

In some embodiments, the present method further comprises assessing apatient's forehead for signs or symptoms of ptosis prior to botulinumtoxin administration botulinum toxin, informing the patient of theexistence of ptosis, and administrating a botulinum toxin to theadministration targets, including the corrugators, procerus, frontalismuscles, or combinations thereof, as disclosed herein.

FIGS. 5A-5D show pictures of various manifestations of ptosis.Manifestations of ptosis comprise a drooping eyelid as shown in FIG. 5A,excessive skin under the brow as shown in FIG. 5B, medial browdepression and/or lateral brow elevation as shown in FIG. 5C. The lidptosis (FIG. 5A), eyebrow ptosis (FIG. 5b ) and medial brow ptosis (FIG.5C) can result from prior botulinum toxin administrations. Senile ptosis(FIG. 5D) can occur independently of prior botulinum toxinadministrations. If the ptosis is due to a prior botulinum toxinadministration, it will resolve over 12 weeks. Senile ptosis, with liddrooping and soft tissue excess around the eyelid, is pre-existing anddoes not change over time.

In some embodiments, the present method prevents non-senile ptosis fromrecurring or senile ptosis from worsening, the method comprises locatingthe administration targets, including the corrugators, the procerus, thefrontalis, or combinations thereof as disclosed herein, isolating theadministration targets so that the botulinum toxin is administered onlyto the intended target area without inadvertently impacting an adjacentarea as disclosed herein; controlling the injection depth, and anglingthe needle as to aim away from sensitive structures, including theperiosteum, as disclosed herein.

In some embodiments, the assessing step comprises inspecting the eyelidand/or the eyebrow of the patient. In some embodiments, the inspectingstep comprises determining whether the eyelid is drooping, whether thereis excessive skin under the brow and whether the eyebrow depresses orelevates. In some embodiments, the present method further comprisesinforming the patient of the existence of the ptosis. In someembodiments, the present method further comprises providing a timeinterval between the assessment step and the administration of thebotulinum toxin to the administration target muscles. In someembodiments, the time interval ranges from 1 week to 5 months. In oneembodiment, the time interval between the assessment step and theadministration step is about 12 weeks. In some embodiments, the timeinterval is less than 12 weeks. In some embodiments, the time intervalis more than 12 weeks. Preferably, as delaying re-treatment maycompromise treatment efficacy, in some embodiments, the present methodcomprises evaluating the patient for ptosis, informing the patient ofthe pre-existing ptosis condition, and administering a botulinum toxinto the target muscles, wherein the administering is specificallytargeted so as to prevent non-senile ptosis from recurring or senileptosis from worsening, as disclosed herein.

In some embodiments, subsequent to the assessing step for pre-existingptosis and informing the patient, the present method further comprisesadministering a botulinum toxin to the target muscles, including and inparticular the corrugators, procerus and frontalis muscles, orcombinations thereof, wherein the target muscles are carefully isolatedas disclosed herein so that the botulinum toxin is administered only tothe intended target area without inadvertently impacting an adjacentarea; and wherein the injection depth is controlled as disclosed herein,and wherein the needle is specifically angled to aim away from sensitivestructures, including the periosteum, as disclosed herein.

Temporalis:

In one exemplary embodiment, the present method further comprises localadministration of a botulinum neurotoxin to the temporalis at aboutforty units divided among eight sites of injection bilaterally, or 4sites on each side (as shown in FIG. 6C) up to fifty units divided amongten sites of injection. The tragus is an important landmark fortemporalis injections. This muscle area commonly bleeds duringinjections because it is surrounded by many blood vessels.

In some embodiments, the present method comprises localizing thetemporalis and administering a botulinum toxin to the temporalis. Insome embodiments, the localizing step comprises locating the tragus. Insome embodiments, the localizing step comprises providing instructionsto a patient to clench his/her teeth, which activates the temporalis. Insome embodiment, the present method comprises localizing a firstadministration site of the temporalis muscle, the localizing stepcomprises locating the tragus and moving a finger vertically up the sideof the head of the patient about 3 cm (or about 2 fingerbreadths) andinjecting the botulinum toxin at the first administration site (FIG.6C). In some embodiments, the present method further compriseslocalizing a second administration site of the temporalis muscle, thelocalizing the second administration site comprises moving vertically inline with the tragus from about 1.5 cm up to about 3 cm (or about 1-2fingerbreadths) from the first administration site, and injecting thebotulinum toxin at the second administration site. In some embodiments,the present method further comprises localizing a third administrationsite of the temporalis muscle, the localizing the third administrationsite comprises moving from about 1.5 cm up to about 3 cm (or about 1-2fingerbreadths) forward toward the face from the first and secondadministration sites and injecting the botulinum toxin at the thirdadministration site. In some embodiments, the present method furthercomprises localizing a fourth administration site of the temporalismuscle, the localizing the fourth administration site comprises movingback about 1.5 cm from the second administration site and in line withthe midportion (helix) of the ear; and injecting the botulinum toxin atthe fourth administration site. In one embodiment, the localizing stepfurther comprises placing a finger in the middle of the helix of the earto locate the fourth administration site. In some embodiments, theadministrating step is carried out as posterior as possible and stayswithin the hairline, as shown in FIG. 6D. In one embodiment, the localadministration of botulinum toxin to the temporalis comprises injectingsuperficially at a 45° angle, as shown in FIG. 6D. In some embodiments,the present method further comprises applying pressure on theadministration site to stop bleeding if bleeding occurs. In someembodiments, the present method further comprises inspecting the patientfollowing administration of the botulinum toxin for bleeding. In someembodiments, the administrating step further comprises drawing back onthe needle to assess for a blood flush in the muscle area. In someembodiments, the penetration depth of the needle is controlled such thatit remains above the periosteum. In some embodiments, a local andtopical anesthetic is administered before administration of theneurotoxin to minimize discomfort.

FIGS. 7A and 7B show the back-of-head and neck anatomy, identifying thelocation of exemplary administration target sites, including theoccipitalis, cervical paraspinal and trapezius muscles. As shown in FIG.7A, several landmarks can be used to localize the administration targetsites. For example, the acromion extends from the spine to the deltoidand can be felt through the skin.

Occipitalis:

In one exemplary embodiment, the present method further comprises localadministration of a botulinum neurotoxin to the occipitalis at aboutthirty units divided among six sites of injection bilaterally, or 3sites on each side (as shown in FIG. 8A) to about forty units dividedamong eight sites of injection. The function of the occipitalis is toserve as an anchor for the frontalis. The occipitalis muscles are inproximity of the occipital nerves, which may cause pain in somepatients. The occipitalis muscle is shallow. If occipitalis injectionsare given too low, they can cause neck pain and weakness. The nuchalridge (FIG. 7B) is an important landmark for occipitalis injections.

In some embodiments, the present method comprises localizing theoccipitalis, and administering a botulinum toxin to the occipitalis. Insome embodiment, the localizing step comprises locating the nuchalridge. The present method comprises localizing a first administrationsite of the occipitalis muscle, the localizing step comprises palpatingthe occipital protuberance and finding the most posterior point, whichis the inion (FIG. 7B); palpating the nuchal ridge and locating the tipof the mastoid process behind the ear (FIG. 7A), placing the thumb onthe midpoint of the occipital protuberance (inion) and the index fingeron the tip of the mastoid process; dividing the space between the thumband the index finger in half and identifying a midpoint; and locatingthe first administration site above the nuchal ridge at the midpoint;and injecting the botulinum toxin at the first administration site. Insome embodiments, the present method further comprises localizing asecond administration site of the occipitalis muscle, the localizing thesecond administration site comprises measuring a diagonal fingerbreadthup and out toward the helix of the ear (at the 10 o'clock position), andinjecting the botulinum toxin at the second administration site. In someembodiments, the present method further comprises localizing a thirdadministration site of the occipitalis muscle, the localizing the thirdadministration site comprises measuring a diagonal fingerbreadth up andmedial (at the 2 o'clock position), and injecting the botulinum toxin atthe third administration site. To prevent low occipitalis injectionswhich can cause neck pain and weakness, in a preferred embodiment, theadministrating step is carried out above the nuchal ridge. In oneembodiment, the local administration of botulinum toxin to theoccipitalis comprises injecting superficially at a 45° angle, as shownin FIG. 8B. In some embodiments, the needle is angled upward, away fromthe neck, as shown in FIG. 8B. In some embodiments, the penetrationdepth of the needle is controlled such that it is just upon penetrationof the dermis. As the occipitalis muscles are in proximity of theoccipital nerves, which may cause pain, in some embodiments, a local andtopical anesthetic is administered before administration of theneurotoxin to minimize discomfort.

Cervical Paraspinal Muscle Group

In one exemplary embodiment, the present method further comprises localadministration of a botulinum neurotoxin to the cervical paraspinalmuscles at about twenty units divided among four sites of injection (asshown in FIG. 9A). The cervical paraspinals should be considered as amuscle group, not a specific muscle. Injecting the cervical paraspinalstoo low or too deep can lead to muscle weakness. To ensure the musclesare not injected too low, the cervical paraspinals should be consideredas suboccipital muscles. In some prior art protocol, the muscle areasfor injection are identified by localizing a first administration siteof the cervical paraspinals, the localizing step comprises measuringabout 1 cm left of the midline of the cervical spine (FIG. 9A) and about3 cm (or about 2 fingerbreadths) inferior to the occipital protuberance(FIG. 7B); and injecting the botulinum toxin at the first administrationsite. A second administration site is identified by measuring about 1.5cm (or about 1 fingerbreadth) diagonally up at a 45° angle toward thehelix of the ear from the first injection; and injecting the botulinumtoxin at the second administration site. Administrating of the botulinumneurotoxin based solely on the approximated distance or fingerbreadthapproach may lead to too low or too deep injections, which can causemuscle weakness.

To minimize or prevent unwarranted side effects, in some embodiments,the present method comprises localizing the cervical paraspinal musclesand administering a botulinum toxin to the cervical paraspinal muscles.In some embodiments, the localizing step comprises visualizing a lineacross the neck, about 2 fingerbreadths down from the occipitalprotuberance and injecting above that line. In some embodiments, thelocalizing step comprises providing instructions to the patient to situpright, with his/her head in a neutral position. If the neck is flexedfar forward, the injections may be too deep. In some embodiments, theadministrating step comprises injecting superficially at a 45° angle, asshown in FIG. 9B. In some embodiments, the administrating occurs in thehairline. In some embodiments, the penetration depth of the needle iscontrolled such that it penetrates the dermis and targets thesuperficial muscle layer.

In some embodiments, the present method further comprises evaluating thepatient for neck weakness and neck pain subsequent to the administratingstep, the evaluating comprises positioning the patient upright, with thehead in the neutral position, determining whether the neck is flexed farforward. If the neck is flexed far forward, the injections may be toodeep. In some embodiments, a local and topical anesthetic isadministered before administration of the neurotoxin to minimizediscomfort.

Trapezius:

In one exemplary embodiment, the present method further comprises localadministration of a botulinum neurotoxin to the trapezius about thirtyunits divided among six sites of injection up (as shown in FIG. 10A) toabout fifty units divided among ten sites of injection. In someembodiments, the present method comprises localizing a firstadministration site of the trapezius, the localizing step comprisesdividing the upper portion of the trapezius muscle in half, from theinflection point of the neck (necklace line) to the acromion (FIG. 7A),the first administration site is located at this midpoint; and injectingthe botulinum toxin at the first administration site. In someembodiments, the present method further comprises localizing a secondadministration site of the trapezius, the localizing the secondadministration site comprises splitting the difference between the firstinjection site and the acromion; and injecting the botulinum toxin atthe second administration site. In some embodiments, the present methodfurther comprises localizing a third administration site of thetrapezius, the localizing the third administration site comprisessplitting the difference between the first injection site and thenecklace line.

To prevent or minimize unwarranted side effects, in some embodiments,the local administration of botulinum toxin to the trapezius comprisesinjecting horizontally to the muscle to avoid injecting too deep, asshown in FIG. 10B. In some embodiments, the local administration ofbotulinum toxin comprises injecting the supraclavicular portion of themuscle, lateral to the necklace line and medial to the deltoid/acromionjoint (FIG. 7A). In some embodiments, a local and topical anesthetic isadministered before administration of the neurotoxin to minimizediscomfort.

In some embodiments, the present method further comprises evaluating thepatient for neck weakness prior to administrating botulinum toxin to thetarget muscles. In some embodiments, the evaluating step comprisespositioning the patient upright, with the head in the neutral positionand determining whether the neck is flexed far forward. If the tragus ofthe ear lines up with the anterior ridge of the trapezius muscle inprofile, as shown in FIG. 11, there is no apparent neck weakness. If thetragus of the ear is more than 2 fingerbreadths (˜3 cm) from theanterior ridge of the trapezius muscle, that shows neck weakness. Insome embodiments, the present method further comprises informing thepatient of the neck weakness. In some embodiments, the present methodfurther comprises providing a time interval between the assessment stepand the administration of the botulinum toxin to the administrationtarget muscles. In some embodiments, the time interval ranges from 1week to 5 months. In one embodiment, the time interval between theassessment step and the administration step is about 12 weeks. In someembodiments, the time interval is less than 12 weeks. In someembodiments, the time interval is more than 12 weeks. Preferably, asdelaying re-treatment may compromise treatment efficacy, in someembodiments, the present method comprises evaluating the patient forneck weakness, informing the patient of the pre-existing neck weaknesscondition, and administering a botulinum toxin to the target muscles,wherein the administering is specifically targeted as to prevent orminimize causing additional neck pain or weakness, as disclosed herein.

In some embodiments, subsequent to the evaluating step for neck weaknessand the informing step, the present method further comprisesadministering a botulinum toxin to the target muscles as disclosedherein, wherein the administering to the cervical paraspinal musclegroup is targeted within two fingerbreadths (˜3 cm) below the occipitalprotuberance (FIG. 7B) and the administering to the trapezius istargeted to the supraclavicular section (corresponding to the injectionsites shown in FIG. 10A) lateral to necklace line (FIG. 7A) to preventor minimize causing additional neck pain or weakness.

The present method can be used to minimize or prevent adverse effectsassociated with the administration of a botulinum toxin for treating,alleviating symptoms, or reducing the occurrence of neuropsychiatricdisorders (ND), including depression, or medication overuse (MOU)disorders.

Significantly, a method within the scope of the present invention canprovide improved patient function. “Improved patient function” can bedefined as an improvement measured by factors such as a reduced pain,reduced time spent in bed, increased ambulation, healthier attitude,more varied lifestyle and/or healing permitted by normal muscle tone.Improved patient function is may be measured with an improved quality oflife (QOL) or Health-Related Quality of Life (HRQL). QOL can beassessed, for example, using the SF-12 or SF-36 health survey scoringprocedures, or the Migraine Specific Quality of Life Questionnarie(MSQ). SF-36 assesses a patient's physical and mental health in theeight domains of physical functioning, role limitations due to physicalproblems, social functioning, bodily pain, general mental health, rolelimitations due to emotional problems, vitality and general healthperceptions. Scores obtained can be compared to published valuesavailable for various general and patient populations. TheMigraine-Specific Quality of Life Questionnaire Version 2.1 is one ofthe most frequently utilized disease-specific tools assessing the impactof migraine on HRQL. The MSQ measures the impact of migraine on thepatient's HRQL over the past 4 weeks across three dimensions: RoleFunction-Restrictive (RR), Role Function-Preventive (RP), and EmotionalFunction (EF). The MSQ was developed from an expert-based item review ofthe migraine literature and validated in a clinical sample of 458 newand stable EM patients. In the validation study the MSQ revealed highinternal consistency (Cronbach's α=0.79 to 0.85), a moderate to strongconvergent validity, as well as an adequate discriminant validity.Martin and Colleagues 21 performed a multi-center study that furthersupported the evidence of a high internal consistency (Cronbach's α=0.86to 0.96), strong reliability and good validity of the 14-item MSQ among267 participants.

The following non-limiting examples provide those of ordinary skill inthe art with specific preferred methods to treat chronic migraine withinthe scope of the present disclosure, and it is not intended to limit thescope of the invention. In the following examples various modes ofnon-systemic administration of a Clostridial neurotoxin can be carriedout. For example, by intramuscular injection, subcutaneous injection orby implantation of a controlled release implant.

EXAMPLES

The following non-limiting examples provide those of ordinary skill inthe art with specific preferred methods to treat conditions within thescope of embodiments of the present invention and are not intended tolimit the scope of the invention.

Example 1

In a clinical study for treatment of chronic migraine byonabotulinumtoxinA using an injection protocol disclosed by the '195patent, it was found that 9% of the patients experienced neck pain and3-4% of the patient experienced ptosis. In a subsequent study at a localheadache center with 100 chronic migraine patients, the followingprotocol was adopted:

The frontalis injections were done in the upper third of the foreheadwith needle angle superiorly at 45 degrees. The needle was insertedbelow the dermis into the superficial muscle layers and not too deep toavoid the periosteum.

The corrugator muscle was injected by having the patient furrow thebrow. The muscle was palpated between the thumb and index finger. Themedial edge of the corrugator muscle was injected. While pinching themuscle to isolate it, the needle was inserted into the muscle at a90-degree angle to the plane of the face. This limited any diffusionfrom the muscle into surrounding areas. The depth of the needle was deepto the dermis, in the superficial muscle, above the periosteum.

Injections into the temporalis muscle can produce temporal wasting. Whenthis occurs in the anterior temporal fossa it produces an hourglassappearance. This was prevented by injecting the temporalis within thehairline, using a vertical line drawn through the tragus of the ear as alandmark for the injections.

If the occipitalis muscle is injected too low it can produce neckweakness and neck pain. To avoid this the muscle was localized asfollows: (a) by placing a finger on the tip of the mastoid process(behind the ear) and a thumb on the inion (most prominent posteriorprotrusion of the skull); (b) splitting the difference between the thumband index finger in half and locating the midpoint on the nuchal ridge.The occipitalis muscle was injected by angling the needle superiorly at45 degrees starting at this point. The injections were below the dermisand above the periosteum.

The cervical paraspinal muscles were injected superficially and high inthe sub-occipital region to avoid neck weakness and neck pain. Theinjection sites were 2 horizontal fingerbreadths (3 cm) below theoccipital protuberance in the midline. The needle was angled superiorlyat 45 degrees, inserted just below the dermis.

The trapezius muscles were injected in the supraclavicular region toavoid neck weakness and neck pain. The trapezius muscle has aninflection point at the necklace line. This was used as a landmarktogether with the acromion. An index finger was placed in the groove ofthe acromion joint and the necklace line. The distance between theacromion and necklace line are split in half for placement of the firstinjection was split in half. At this point the first injection was done,at a 0 to 45° angle to avoid a deep injection. The injection was justbelow the dermis in the superficial muscle layers. The second and thirdinjections were done medial and lateral to the first in an equidistantfashion.

The adverse event rates for the 100 patients receiving theabove-described protocol were 1% for the brow ptosis and 4% for the neckpain.

Example 2

A 50 year old woman with CM has been injected with onabotulinumtoxinA byanother neurologist on one occasion. She reported that her brow wasdepressed and her neck was weak with associated pain. This developed 2weeks after her treatment and persisted for 6 weeks before graduallyresolving. She wanted to continue onabotulinumtoxinA treatment for CMbut did not want her neck/shoulder or forehead regions to bere-injected.

After educating the patient about the injection protocol described inExample 1 with careful attention to the portion of the muscles that needto be injected to maximize efficacy and decrease side effects, sheagreed to proceed. The protocol described in Example 1 was used to treather. She returned at 6 weeks and reported no brow ptosis or neck pain.Her headaches were reducing and she was satisfied to continue forward toher third onabotulinumtoxinA treatment in 6 week time.

Many alterations and modifications may be made by those having ordinaryskill in the art, without departing from the spirit and scope of thedisclosure. Therefore, it must be understood that the describedembodiments have been set forth only for the purposes of examples, andthat the embodiments should not be taken as limiting the scope of thefollowing claims. The following claims are, therefore, to be read toinclude not only the combination of elements which are literally setforth, but all equivalent elements for performing substantially the samefunction in substantially the same way to obtain substantially the sameresult. The claims are thus to be understood to include those that havebeen described above, those that are conceptually equivalent, and thosethat incorporate the ideas of the disclosure.

We claim:
 1. A method for alleviating or reducing the occurrence of aheadache in a patient with chronic migraine headaches, the methodcomprises: localizing one or more administration targets; isolating theone or more administration targets; wherein the isolating step isolatesthe one or more administration targets from an adjacent area;administering a therapeutically effective amount of a clostridial toxinto the one or more isolated administration targets; wherein the one ormore administration targets comprise the frontalis, corrugator,procerus, occipitalis, temporalis, trapezius and cervical paraspinalmuscles; wherein the administrating step is by injection and wherein theadministering step comprises injecting superficially at a 90° angle intothe corrugator muscles; thereby alleviating or reducing the occurrenceof the headache in the patient.
 2. The method of claim 1, wherein theisolating the corrugator muscle comprises providing instructions to thepatient to furrow her/his brow, palpating and pinching the corrugatormuscle, holding the corrugator muscle between the thumb and indexfinger.
 3. The method of claim 1, wherein the isolating the procerusmuscle comprises providing instructions to the patient to furrow her/hisbrow, using the resulting vertical and horizontal lines as orientationlines.
 4. The method of claim 1, wherein the administering to theprocerus muscle comprises targeting the belly of the procerus muscle,injecting superficially at a 90° angle into the procerus, andcontrolling the penetration depth of the needle such that it remainsabove the periosteum.
 5. The method of claim 1, wherein the isolatingthe frontalis muscle comprises providing instructions to the patient toraising her/his eyebrows and skin over the root of the nose in anattempt to create an expression of surprise and identifying the upperthird of the forehead.
 6. The method of claim 1, wherein theadministrating step to the frontalis comprises angling the needlesuperiorly at a 45° angle into the frontalis muscle and injectingsuperficially by controlling the penetration depth of the needle suchthat it remains above the periosteum.
 7. The method of claim 1, whereinthe localizing the cervical paraspinal muscles comprises providinginstructions to the patient to sit upright, with his/her head in aneutral position, visualizing a line across the patient's neck about 2fingerbreadths down from the occipital protuberance.
 8. The method ofclaim 7, wherein the administrating step to the cervical paraspinalcomprises injecting superficially at a 45° angle above the visualizedline about 2 fingerbreadths down from the patient's occipitalprotuberance.
 9. The method of claim 1, wherein the administrating tothe trapezius muscle comprises injecting horizontally to the trapeziusmuscle.
 10. The method of claim 1, wherein the administrating to thetrapezius muscle comprises injecting the supraclavicular portion of themuscle, lateral to the necklace line and medial to the deltoid/acromionjoint.
 11. The method of claim 1, wherein the clostridial toxin is abotulinum toxin.
 12. A method for minimizing adverse effects associatedwith the administration of a clostridial toxin for treating oralleviating a headache in a patient with chronic migraine, the methodcomprises locating one or more administration targets, isolating the oneor more administration targets, administering a therapeuticallyeffective amount of a clostridial toxin to the one or more isolatedadministration targets; wherein the one or more administration targetscomprise the frontalis, corrugator, procerus, occipitalis, temporalis,trapezius and cervical paraspinal muscles; wherein the isolating stepisolates the one or more administration targets from an adjacent area;and wherein the administrating step comprises injecting superficially ata 90° angle into the corrugator muscles; thereby minimizing adverseeffects associated with the administration of the clostridial toxin. 13.The method of claim 12, wherein the adverse effects comprise ptosis,neck pain and/or weakness, headache, or combinations thereof.
 14. Themethod of claim 12, wherein the clostridial toxin is a botulinum toxin.15. A method for improving efficacy of headache treatment by aclostridial toxin in a patient in need thereof by minimizing one or moreadverse effects associated with clostridial toxin administration,comprising localizing one or more administration targets, isolating theone or more administration targets, administering a therapeuticallyeffective amount of the clostridial toxin to the isolated one or moreadministration targets; wherein the isolating step isolates the one ormore administration targets from an adjacent area; wherein the one ormore administration targets comprise the frontalis, corrugator,procerus, occipitalis, temporalis, trapezius and cervical paraspinalmuscles; and wherein the administrating comprises injectingsuperficially at a 90° angle into the belly of the corrugator muscles;thereby preventing or minimizing unwarranted adverse effects andimproving efficacy of headache treatment.
 16. The method of claim 15,wherein the adverse effects comprise ptosis, neck pain, neck weakness,headaches, or combinations thereof.
 17. The method of claim 15, furthercomprising evaluating the patient of manifestation of the one or moreadverse effects prior to the localizing, isolating and administratingsteps.
 18. The method of claim 15, wherein the clostridial toxin is abotulinum toxin.
 19. A method for treating or reducing the occurrence ofa headache in a patient with chronic migraine headaches, the methodcomprising: local administration of a botulinum neurotoxin to 31 fixedinjection sites across seven head and neck muscles, and optionally up to8 additional injection sites into three specific muscles, wherein thesethree muscles are subset of the seven head and neck muscles, wherein the31 fixed injection sites comprise the frontalis, corrugator, procerus,occipitalis, temporalis, trapezius and cervical paraspinal muscles; andwherein the administration is by injection and comprises injectingsuperficially at a 90° angle into the corrugator muscles; therebyalleviating or reducing the occurrence of the headache in the patient;to thereby treat or reduce the occurrence of chronic migraine headachein the patient.
 20. The method of claim 19, wherein the botulinumneurotoxin is serotype A.
 21. The method of claim 20, wherein thebotulinum neurotoxin type A is onabotulinumtoxinA.
 22. The method ofclaim 21, wherein the total amount of botulinum toxin type Aadministered is from about 155 units to about 195 units ofonabotulinumtoxinA.
 23. The method of claim 20, wherein the botulinumneurotoxin type A is abobotulinumtoxinA.
 24. The method of claim 19,wherein the botulinum neurotoxin is a pure botulinum toxin.
 25. Themethod of claim 24, wherein the pure botulinum neurotoxin isincobotulinumtoxinA.
 26. The method of claim 19, wherein the botulinumneurotoxin is serotype B.
 27. The method of claim 19, wherein thebotulinum neurotoxin is type E.
 28. The method of claim 19, wherein theadministration is by subcutaneous injection.
 29. The method of claim 19,wherein the administration is by intramuscular injection.